Gallium is known as a second chemotherapy agent, after platinum, due to its high and specific affinity toward tumour tissues. The readiness of the radioactive isotope 68Ga to couple to small biomolecules makes it a potential alternative to 18F and 11C in PET applications. Several chelate compounds developed for radiolabelling of peptides and/or protein entities with metallic radionuclides are well suited to 68Ga labelling.
68Ga is a second important β+ emitter after 18F and may be efficiently used in PET imaging. It is characterised by high position abundance and good imaging resolution. 89.14% of 68Ga atoms decay with emission of β+ particles (with the 511 KeV annihilation gamma ray intensity of 178.2%). The 829.5 KeV positron radiation provides a PET imaging resolution of about 2.3 mm (bone)-11.5 mm (lung) for living tissues (compared to 0.65 mm-2.7 mm in the case of 18F). These values lie well within the system resolution of modern PET cameras (4-5 mm) and even with high resolution PET system (3 mm).
An advantage of use of 68Ga is that it has no associated gamma impact on PET images. Insignificant amount of associated gamma emissions (0.03407%) from 68Ga fall into the commonly used PET energy window of 350 to 700 KeV, and so it has almost no impact on PET images. A further advantage is that 68Ga has good conformation to conventional radiation safety. The Γ20 KeV exposure rate constant is 0.179 μSv·m2/MBq·h (compared to 0.188 μSv·m2/MBq·h for 18F), thus the use of 18F standard radiation safety automatic infusion systems is feasible. An additional benefit is its cost-effectiveness and on-demand availability. The long-lived parent nuclide 68Ge offers a cost-effective precursor for PET imaging applications with a generator shelf-life of about 2 years. 68Ge/68Ga generators also render the 68Ga based PET radiopharmacy independent of an onsite cyclotron. This means that this generator is ideally suited to on-demand availability of β+ emitters for biomedical experiments and clinical targeting imaging, both in remote PET centres without a cyclotron and also in cyclotron-operating PET centres.
68Ga is suitable for kit formulation. It is predicted that 68Ga may become widely used for PET/CT. Kit formulated precursors along with 68Ga generators may be provided, similar to the 99mTc—in vivo kits, making such generators the mainstay of molecular imaging nuclear medicine in the future.
Demand for a suitable 68Ga generator in the world market is high and increasing. In 2008, more than 50 PET centres in Europe and over 20 in the Asia Pacific region (4 in Australia) used 68Ga generators for clinical purposes. The high price of Ga-68 generators is a convincing indicator that domestic production/supply of such generators where a proton bombardment facility is available may be commercially viable.
Presently 68Ga is used for the preparation of molecular imaging radiopharmaceuticals used for clinical diagnoses and therapy, especially for cancer treatment. For this purpose 68Ga solution should be concentrated and free of metallic ionic impurities. Currently 68Ga solution or 68Ga eluate is produced from a 68Ge/68Ga generator which is commercially available. 68Ga eluate from current generators is commonly of low 68Ga concentration and contains a sufficiently high content of metallic ion impurities that preparation of radiopharmaceuticals is impossible. There is therefore a need for a pure 68Ga solution of high concentration. Such a solution is a pre-requisite for the successful diagnosis and treatment in modern nuclear medicine.
Processes for the purification and concentration of 68Ga eluate have been developed. One such method uses a strong anionic exchanger resin column for separation and purification. The 68Ga eluate in this process is adjusted with 8 M HCl solution to 4M HCl before loading onto resin column. 68Ga retained on this column is then eluted with a small volume of distilled water (F. Mourtada et al., United States Patent No. US 2008/0035542 A1 Feb. 14, 2008; I. Velikyan et al., Bioconjugate Chem., 15, 554-560, (2004)). This method is not capable of removing some important metallic ion impurities, such as Fe3+ and Zn2+. Also, the apparatus used in the method is complex and sophisticated, and is not amenable to use by non-professional users. Another purification and concentration method has been reported and is currently used, based on retention of 68Ga3+ ions of 68Ga eluate on a strong cationic ion exchange resin column, and subsequent removal of co-adsorbed impure metallic ions by washing the column with 0.15 M HCl solution containing 80% acetone. Finally, 68Ga ions are eluted from the resin column with a small volume of 0.015 M HCl solution containing 98% acetone. This method is successful for removing the majority of impure metallic ions, including Fe3+ and Zn2+. Unfortunately, the acetone solvent readily reacts with the HCl solution to form a polymeric product. Consequently, the purification process will be unsuccessful if the history of the acetone/HCl solution is unknown. The polymeric residue present in the 68GaCl3 preparation after evaporation of the acetone will affect the labelling radiopharmaceuticals which is usually a biomedical substance. All steps of this purification process were performed manually.
There is therefore a need for an improved method to purify and concentrate Ga-68 for radiopharmaceutical use, and for a simple automated system for conducting the method.